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Role of Dietary Salt and Potassium Intake in Cardiovascular Health and Disease: A Review of the Evidence

      Abstract

      The objective of this review was to provide a synthesis of the evidence on the effect of dietary salt and potassium intake on population blood pressure, cardiovascular disease, and mortality. Dietary guidelines and recommendations are outlined, current controversies regarding the evidence are discussed, and recommendations are made on the basis of the evidence. Designed search strategies were used to search various databases for available studies. Randomized trials of the effect of dietary salt intake reduction or increased potassium intake on blood pressure, target organ damage, cardiovascular disease, and mortality were included. Fifty-two publications from January 1, 1990, to January 31, 2013, were identified for inclusion. Consideration was given to variations in the search terms used and the spelling of terms so that studies were not overlooked, and search terms took the following general form: (dietary salt or dietary sodium or [synonyms]) and (dietary potassium or [synonyms]) and (blood pressure or hypertension or vascular disease or heart disease or chronic kidney disease or stroke or mortality or [synonyms]). Evidence from these studies demonstrates that high salt intake not only increases blood pressure but also plays a role in endothelial dysfunction, cardiovascular structure and function, albuminuria and kidney disease progression, and cardiovascular morbidity and mortality in the general population. Conversely, dietary potassium intake attenuates these effects, showing a linkage to reduction in stroke rates and cardiovascular disease risk. Various subpopulations, such as overweight and obese individuals and aging adults, exhibit greater sensitivity to the effects of reduced salt intake and may gain the most benefits. A diet that includes modest salt restriction while increasing potassium intake serves as a strategy to prevent or control hypertension and decrease cardiovascular morbidity and mortality. Thus, the body of evidence supports population-wide sodium intake reduction and recommended increases in dietary potassium intake as outlined by current guidelines as an essential public health effort to prevent kidney disease, stroke, and cardiovascular disease.

      Abbreviations and Acronyms:

      BP (blood pressure), CKD (chronic kidney disease), CVD (cardiovascular disease), DASH (Dietary Approaches to Stop Hypertension), RCT (randomized controlled trial), UNa (urinary sodium)
      Article Highlights
      • Evidence from multiple randomized trials reinforces a role for increased dietary salt intake in the elevation of blood pressure as well as endothelial dysfunction, vascular remodeling and dysregulation, albuminuria and kidney disease progression, and cardiovascular morbidity and mortality in the general population.
      • Dietary potassium supplementation attenuates the effects of high dietary salt intake, showing a linkage to reduced blood pressure, stroke rates, and cardiovascular disease risk.
      • Modest dietary salt restriction accompanied by increasing potassium intake serves as a broad-spectrum strategy to prevent or control hypertension and decrease cardiovascular morbidity and mortality.
      • As outlined by current guidelines in the United States, population-wide sodium intake reduction and recommended increases in dietary potassium intake provide an essential public health effort to reduce rates of hypertension and prevent kidney disease, stroke, and cardiovascular disease.
      • Presently, the evidence base is insufficient to determine a lower limit for dietary salt intake and an upper limit for dietary potassium intake.
      During the past century, medical research in the United States has undergone a classic epidemiologic transition,
      • Omran A.R.
      The epidemiologic transition: a theory of the epidemiology of population change: 1971.
      with the focus shifting from public health issues related to childhood infectious diseases, nutrient deficiencies, and epidemics to noncommunicable diseases, including cardiovascular disease (CVD), hypertension, diabetes mellitus, and chronic kidney disease (CKD). Although these diseases may have a genetic predisposition, there is a strong association with environmental influences, suggesting that they are lifestyle related. The problem is enormous: in 2009-2010, for example, 23.1% of adult Americans had prehypertension, and an additional 29.5% had hypertension.
      • Yoon S.S.
      • Burt V.
      • Louis T.
      • Carroll M.D.
      Hypertension among adults in the United States, 2009-2010.
      Estimates projected by the American Heart Association place the direct and indirect costs of hypertension at more than $93.5 billion per year.
      • Heidenreich P.A.
      • Trogdon J.G.
      • Khavjou O.A.
      • et al.
      Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.
      Population studies have reported an association between dietary sodium chloride (termed salt in this review) intake as well as dietary potassium intake and blood pressure (BP).
      • Tzoulaki I.
      • Patel C.J.
      • Okamura T.
      • et al.
      A nutrient-wide association study on blood pressure.
      Intersalt Cooperative Research Group
      Intersalt: an international study of electrolyte excretion and blood pressure: results for 24 hour urinary sodium and potassium excretion.
      • Cook N.R.
      • Cutler J.A.
      • Obarzanek E.
      • et al.
      Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the Trials of Hypertension Prevention (TOHP).
      • Cook N.R.
      • Obarzanek E.
      • Cutler J.A.
      • et al.
      Joint effects of sodium and potassium intake on subsequent cardiovascular disease: the Trials of Hypertension Prevention follow-up study.
      • Espeland M.A.
      • Kumanyika S.
      • Yunis C.
      • et al.
      Electrolyte intake and nonpharmacologic blood pressure control.
      • Saint-Remy A.
      • Somja M.
      • Gellner K.
      • Weekers L.
      • Bonvoisin C.
      • Krzesinski J.M.
      Urinary and dietary sodium and potassium associated with blood pressure control in treated hypertensive kidney transplant recipients: an observational study.
      Because of the increasing prevalence of hypertension and CVD, nonpharmacological dietary guidelines designed to promote the health of the public have, therefore, been instituted.
      • Mozaffarian D.
      • Ludwig D.S.
      Dietary guidelines in the 21st century: a time for food.
      Although these programs have an impact, most Americans consume well above the minimum daily requirement for dietary salt and, further, have inadequate potassium intake. To emphasize the excess salt in the American diet, the US Department of Health and Human Services/US Department of Agriculture 2010 Dietary Guidelines advise Americans to reduce daily sodium intake to less than 2300 mg/d per person, with an even lower goal of 1500 mg/d for specific subpopulations; the Institute of Medicine has recommended an age-dependent targeted sodium intake of 1000 to 1500 mg/d and established a tolerable upper level of intake of 1500 to 2300 mg/d.
      Between 2003 and 2008, median daily sodium intake excluding table salt was 3371 mg (interquartile range, 2794-4029 mg) and median potassium consumption was 2631 mg (interquartile range, 2164-3161 mg) in US adults older than 20 years; 99.4% of US adults consumed more than 1500 mg of sodium daily, and 90.7% consumed more than 2300 mg/d.
      • Cogswell M.E.
      • Zhang Z.
      • Carriquiry A.L.
      • et al.
      Sodium and potassium intakes among US adults: NHANES 2003-2008.
      Recent high-profile publications, however, have challenged these guidelines. For this reason, this study considered the evidence that the level of dietary salt and potassium intake affects population BP, CVD, and mortality. Specifically, we examined the scientific rationale for population-wide recommendations to increase dietary potassium intake while reducing salt intake and the strength of available evidence, and we offer recommendations for stakeholders to consider.

      Methods and Evidence Base

      Studies in this review include randomized controlled trials (RCTs) linking dietary salt and potassium intakes to subsequent morbidity and mortality, which determine the health outcomes of reducing salt intake and increasing potassium intake by diet or supplementation. The following databases (January 1, 1990, to January 31, 2013) were examined: Cochrane Central Register of Controlled Trials, MEDLINE (Pubmed and Quertle), EMBASE, Cumulative Index to Nursing & Allied Health Literature, Database of Abstracts of Reviews of Effects, the Turning Research Into Practice database, EBSCOhost, Scopus, and ClinicalTrials.gov. Consideration was given to variations in the search terms used and the spelling of terms so that studies were not overlooked, and search terms took the following general form: (dietary salt or dietary sodium or [synonyms]) and (dietary potassium or [synonyms]) and (blood pressure or hypertension or vascular disease or heart disease or chronic kidney disease or stroke or mortality or [synonyms]). Studies were excluded if (1) the article described an observational or ecological study, a review, or an editorial/commentary; (2) the language was not English; (3) the total number of participants was less than 20; or (4) the outcome of the trial did not include systolic and diastolic BP, markers of renal damage, CKD, markers and indices of vascular function, CVD and CVD-related hospital admissions, or mortality. Studies that examined outcomes in the setting of heart failure were also excluded.
      Studies were selected for inclusion on the basis of the following criteria:
      • Study design: RCTs
      • Types of participants: children and adults, irrespective of sex or ethnicity; studies of pregnant women were excluded
      • Studies had to include an assessment of dietary salt or potassium intake and could involve participants receiving a dietary intervention that restricted salt intake, one in which the intervention was advice to reduce salt intake, or one that increased dietary potassium intake or involved potassium supplementation; dietary salt or potassium intake could be assessed by dietary recall, measurement of dietary intake or supplement use in an intervention, or laboratory assessment of urinary sodium (UNa) and potassium levels because both track closely with dietary intakes
      • Comparator: control, placebo, or no intervention
      The titles and abstracts of studies identified by the search strategy were independently screened by the authors, and clearly irrelevant studies were discarded. For inclusion, abstracts had to identify the study design, an appropriate population, and a relevant intervention/exposure, as described previously herein. The full-text reports of all potentially relevant studies were obtained and assessed independently for eligibility by both authors based on the defined inclusion criteria. Standardized data extraction forms were used, and relevant data were extracted by a single reviewer (K.J.A.) and checked by a second reviewer (P.W.S.). Any disagreement was resolved by discussion. Extracted outcomes at the latest follow-up point in the trial and at the latest follow-up after the trial, when available, were used to maximize the number of events reported. The methodological quality of evidence provided by the included studies was graded using published guidelines (Table 1).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      • Uhlig K.
      • Macleod A.
      • Craig J.
      • et al.
      Grading evidence and recommendations for clinical practice guidelines in nephrology: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
      Although RCTs were initially graded “A,” the grade was reduced by inherent limitations of the trial, such as short study duration, small number of study participants that might limit the applicability of the findings to the population as a whole, and experimental bias.
      Table 1Definitions of the Grades Assigned to the Evidence Presented in This Review
      GradeQuality of the evidenceMeaning
      AHighFurther research is unlikely to change the confidence in the estimate of the effect
      BModerateFurther research is likely to affect the confidence in the estimate of the effect and may change the estimate
      CLowFurther research is very likely to have an important effect on the confidence in the estimate of the effect and is likely to change the estimate
      DVery lowThe estimate of the effect is very uncertain
      Although many of the studies included in this review were of high quality, the combined data are difficult to group together for analysis because of inherent variations in (1) the targeted level of dietary salt intake, (2) the choice of a control population, (3) the duration of the studies, (4) the sex and race of the study population, (5) the underlying organ injury, and (6) the selected end points. Moreover, some studies had small numbers of participants, and although the study may have been well done, the ability to generalize the findings to an entire population may not be feasible. Finally, most available studies focused specifically on BP changes and not on other clinically important end points, such as target organ damage and mortality. Nevertheless, the studies offer some recommendations to consider, and these recommendations are graded in a standard manner (Table 2).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      • Uhlig K.
      • Macleod A.
      • Craig J.
      • et al.
      Grading evidence and recommendations for clinical practice guidelines in nephrology: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
      Table 2Levels of the Strength of the Recommendations Provided in This Review
      LevelImplications for patientsImplications for clinicians
      1Most people in your situation would want the recommended course of action, and only a small proportion would notMost patients should receive the recommended course of action
      2Most people in your situation would want the recommended course of action, but many would notDifferent choices will be appropriate for different patients. Each patient needs help to arrive at a management decision that is consistent with the individual patient's characteristics

      Results

      From the literature evaluated, 52 studies met the criteria for this review (Table 3 and Supplemental Table [available online at http://www.mayoclinicproceedings.org]). Of these studies, 28 involved modification of dietary salt intake,
      Trials of Hypertension Prevention Collaborative Research Group
      Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Applegate W.B.
      • Miller S.T.
      • Elam J.T.
      • et al.
      Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension.
      • Blumenthal J.A.
      • Babyak M.A.
      • Hinderliter A.
      • et al.
      Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study.
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • Haythornthwaite J.A.
      • Pratley R.E.
      • Anderson D.E.
      Behavioral stress potentiates the blood pressure effects of a high sodium intake.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Jessani S.
      • Hatcher J.
      • Chaturvedi N.
      • Jafar T.H.
      Effect of low vs. high dietary sodium on blood pressure levels in a normotensive Indo-Asian population.
      • Johnson A.G.
      • Nguyen T.V.
      • Davis D.
      Blood pressure is linked to salt intake and modulated by the angiotensinogen gene in normotensive and hypertensive elderly subjects.
      • Jula A.M.
      • Karanko H.M.
      Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild-to-moderate essential hypertension.
      • Kojuri J.
      • Rahimi R.
      Effect of “no added salt diet” on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension.
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      DASH-Sodium Collaborative Research Group
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      • Schorr U.
      • Turan S.
      • Distler A.
      • Sharma A.M.
      Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men.
      • Sciarrone S.E.
      • Beilin L.J.
      • Rouse I.L.
      • Rogers P.B.
      A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Svetkey L.P.
      • Simons-Morton D.G.
      • Proschan M.A.
      • et al.
      Effect of the Dietary Approaches to Stop Hypertension diet and reduced sodium intake on blood pressure control.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • van Berge-Landry H.
      • James G.D.
      Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load.
      • Vollmer W.M.
      • Sacks F.M.
      • Ard J.
      • et al.
      Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      • Cappuccio F.P.
      • Markandu N.D.
      • Carney C.
      • Sagnella G.A.
      • MacGregor G.A.
      Double-blind randomised trial of modest salt restriction in older people.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Dishy V.
      • Sofowora G.G.
      • Imamura H.
      • et al.
      Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.
      • Maruthur N.M.
      • Wang N.Y.
      • Appel L.J.
      Lifestyle interventions reduce coronary heart disease risk: results from the PREMIER Trial.
      • Vaidya A.
      • Bentley-Lewis R.
      • Jeunemaitre X.
      • Adler G.K.
      • Williams J.S.
      Dietary sodium alters the prevalence of electrocardiogram determined left ventricular hypertrophy in hypertension.
      12 involved modification of dietary potassium intake,
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      • Smith S.R.
      • Klotman P.E.
      • Svetkey L.P.
      Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.
      • Whelton P.K.
      • Buring J.
      • Borhani N.O.
      • et al.
      Trials of Hypertension Prevention (TOHP) Collaborative Research Group
      The effect of potassium supplementation in persons with a high-normal blood pressure: results from phase I of the Trials of Hypertension Prevention (TOHP).
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • Brancati F.L.
      • Appel L.J.
      • Seidler A.J.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in African Americans on a low-potassium diet: a randomized, double-blind, placebo-controlled trial.
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • Gu D.
      • He J.
      • Wu X.
      • Duan X.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in Chinese: a randomized, placebo-controlled trial.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      • Patki P.S.
      • Singh J.
      • Gokhale S.V.
      • Bulakh P.M.
      • Shrotri D.S.
      • Patwardhan B.
      Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study.
      and 12 involved modification of both dietary salt and potassium intake
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, Phase I.
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Cook N.R.
      • Kumanyika S.K.
      • Cutler J.A.
      Effect of change in sodium excretion on change in blood pressure corrected for measurement error: the Trials of Hypertension Prevention, Phase I.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      • Nowson C.A.
      • Morgan T.O.
      • Gibbons C.
      Decreasing dietary sodium while following a self-selected potassium-rich diet reduces blood pressure.
      • Sarkkinen E.S.
      • Kastarinen M.J.
      • Niskanen T.H.
      • et al.
      Feasibility and antihypertensive effect of replacing regular salt with mineral salt-rich in magnesium and potassium in subjects with mildly elevated blood pressure.
      • Whelton P.K.
      • Kumanyika S.K.
      • Cook N.R.
      • et al.
      Trials of Hypertension Prevention Collaborative Research Group
      Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention.
      • Chang H.Y.
      • Hu Y.W.
      • Yue C.S.
      • et al.
      Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men.
      (Table 3 and Supplemental Table [available online at http://www.mayoclinicproceedings.org]). Of the 28 publications in which dietary salt intake was adjusted, 24 studies with 4019 participants receiving an intervention, 3714 controls, and approximate median follow-up of 3.5 months reported outcomes for systolic BP15-38; 23 studies with 3969 participants receiving an intervention, 3580 controls, and approximate median follow-up of 3.5 months reported outcomes for diastolic BP15-22,24-38; 3 studies with 640 participants receiving an intervention, 715 controls, and approximate median follow-up of 2 months reported outcomes for mean arterial pressure
      • Haythornthwaite J.A.
      • Pratley R.E.
      • Anderson D.E.
      Behavioral stress potentiates the blood pressure effects of a high sodium intake.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Dishy V.
      • Sofowora G.G.
      • Imamura H.
      • et al.
      Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.
      ; 3 studies with 273 participants receiving an intervention, 228 controls, and approximate median follow-up of 1.5 months reported outcomes for ambulatory BP.
      • Kojuri J.
      • Rahimi R.
      Effect of “no added salt diet” on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension.
      • Schorr U.
      • Turan S.
      • Distler A.
      • Sharma A.M.
      Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men.
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      Of the 12 publications in which dietary salt and potassium were adjusted, 11 studies with 2713 participants receiving an intervention, 2430 controls, and approximate median follow-up of 12 months reported outcomes for systolic and diastolic BP
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, Phase I.
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Cook N.R.
      • Kumanyika S.K.
      • Cutler J.A.
      Effect of change in sodium excretion on change in blood pressure corrected for measurement error: the Trials of Hypertension Prevention, Phase I.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      • Nowson C.A.
      • Morgan T.O.
      • Gibbons C.
      Decreasing dietary sodium while following a self-selected potassium-rich diet reduces blood pressure.
      • Sarkkinen E.S.
      • Kastarinen M.J.
      • Niskanen T.H.
      • et al.
      Feasibility and antihypertensive effect of replacing regular salt with mineral salt-rich in magnesium and potassium in subjects with mildly elevated blood pressure.
      • Whelton P.K.
      • Kumanyika S.K.
      • Cook N.R.
      • et al.
      Trials of Hypertension Prevention Collaborative Research Group
      Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention.
      (Table 3). The most compelling evidence of the dose-response relationship between salt and BP came from rigorously controlled trials in which more than 2 levels of salt diets were implemented, such as the seminal work by MacGregor et al
      • MacGregor G.A.
      • Markandu N.D.
      • Sagnella G.A.
      • Singer D.R.
      • Cappuccio F.P.
      Double-blind study of three sodium intakes and long-term effects of sodium restriction in essential hypertension.
      and the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial.
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      DASH-Sodium Collaborative Research Group
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      In adults with prehypertension or stage 1 hypertension in the DASH-Sodium trial, a clear dose-response relationship was found in the general American diet and in the DASH diet when salt intake was reduced from 8 to 6 and to 4 g/d; and, the decrease in BP was greater at a lower level of salt intake (ie, from 6 to 4 g/d compared with that from 8 to 6 g/d).
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      DASH-Sodium Collaborative Research Group
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      Other large, well-designed RCTs, including the Trials of Hypertension Prevention I and II56,59,65 and the Trial of Nonpharmacologic Interventions in the Elderly,
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      have reinforced the important role of salt intake in determining the levels of BP in the populations under study. Additional RCTs have also lent support to reduction of salt intake in specific populations.
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Cappuccio F.P.
      • Markandu N.D.
      • Carney C.
      • Sagnella G.A.
      • MacGregor G.A.
      Double-blind randomised trial of modest salt restriction in older people.
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      Table 3Randomized Clinical Trial Characteristics by Intervention and Outcome
      InterventionStudies (No.)Participants receiving an intervention (No.)Controls (No.)Follow-up (median [mo])
      Assessed systolic blood pressure
       Dietary salt intake adjustment
      Trials of Hypertension Prevention Collaborative Research Group
      Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Applegate W.B.
      • Miller S.T.
      • Elam J.T.
      • et al.
      Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension.
      • Blumenthal J.A.
      • Babyak M.A.
      • Hinderliter A.
      • et al.
      Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study.
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • Haythornthwaite J.A.
      • Pratley R.E.
      • Anderson D.E.
      Behavioral stress potentiates the blood pressure effects of a high sodium intake.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Jessani S.
      • Hatcher J.
      • Chaturvedi N.
      • Jafar T.H.
      Effect of low vs. high dietary sodium on blood pressure levels in a normotensive Indo-Asian population.
      • Johnson A.G.
      • Nguyen T.V.
      • Davis D.
      Blood pressure is linked to salt intake and modulated by the angiotensinogen gene in normotensive and hypertensive elderly subjects.
      • Jula A.M.
      • Karanko H.M.
      Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild-to-moderate essential hypertension.
      • Kojuri J.
      • Rahimi R.
      Effect of “no added salt diet” on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension.
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      DASH-Sodium Collaborative Research Group
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      • Schorr U.
      • Turan S.
      • Distler A.
      • Sharma A.M.
      Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men.
      • Sciarrone S.E.
      • Beilin L.J.
      • Rouse I.L.
      • Rogers P.B.
      A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Svetkey L.P.
      • Simons-Morton D.G.
      • Proschan M.A.
      • et al.
      Effect of the Dietary Approaches to Stop Hypertension diet and reduced sodium intake on blood pressure control.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • van Berge-Landry H.
      • James G.D.
      Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load.
      • Vollmer W.M.
      • Sacks F.M.
      • Ard J.
      • et al.
      Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      • Cappuccio F.P.
      • Markandu N.D.
      • Carney C.
      • Sagnella G.A.
      • MacGregor G.A.
      Double-blind randomised trial of modest salt restriction in older people.
      24401937143.5
       Dietary potassium intake adjustment
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • Brancati F.L.
      • Appel L.J.
      • Seidler A.J.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in African Americans on a low-potassium diet: a randomized, double-blind, placebo-controlled trial.
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • Gu D.
      • He J.
      • Wu X.
      • Duan X.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in Chinese: a randomized, placebo-controlled trial.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      • Patki P.S.
      • Singh J.
      • Gokhale S.V.
      • Bulakh P.M.
      • Shrotri D.S.
      • Patwardhan B.
      Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study.
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      • Smith S.R.
      • Klotman P.E.
      • Svetkey L.P.
      Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.
      • Whelton P.K.
      • Buring J.
      • Borhani N.O.
      • et al.
      Trials of Hypertension Prevention (TOHP) Collaborative Research Group
      The effect of potassium supplementation in persons with a high-normal blood pressure: results from phase I of the Trials of Hypertension Prevention (TOHP).
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      127527852.5
       Both salt and potassium intake adjustments
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, Phase I.
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Cook N.R.
      • Kumanyika S.K.
      • Cutler J.A.
      Effect of change in sodium excretion on change in blood pressure corrected for measurement error: the Trials of Hypertension Prevention, Phase I.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      • Nowson C.A.
      • Morgan T.O.
      • Gibbons C.
      Decreasing dietary sodium while following a self-selected potassium-rich diet reduces blood pressure.
      • Sarkkinen E.S.
      • Kastarinen M.J.
      • Niskanen T.H.
      • et al.
      Feasibility and antihypertensive effect of replacing regular salt with mineral salt-rich in magnesium and potassium in subjects with mildly elevated blood pressure.
      • Whelton P.K.
      • Kumanyika S.K.
      • Cook N.R.
      • et al.
      Trials of Hypertension Prevention Collaborative Research Group
      Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention.
      112713243012.0
      Assessed diastolic blood pressure
       Dietary salt intake adjustment
      Trials of Hypertension Prevention Collaborative Research Group
      Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Applegate W.B.
      • Miller S.T.
      • Elam J.T.
      • et al.
      Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension.
      • Blumenthal J.A.
      • Babyak M.A.
      • Hinderliter A.
      • et al.
      Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study.
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • Haythornthwaite J.A.
      • Pratley R.E.
      • Anderson D.E.
      Behavioral stress potentiates the blood pressure effects of a high sodium intake.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Johnson A.G.
      • Nguyen T.V.
      • Davis D.
      Blood pressure is linked to salt intake and modulated by the angiotensinogen gene in normotensive and hypertensive elderly subjects.
      • Jula A.M.
      • Karanko H.M.
      Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild-to-moderate essential hypertension.
      • Kojuri J.
      • Rahimi R.
      Effect of “no added salt diet” on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension.
      • Sacks F.M.
      • Svetkey L.P.
      • Vollmer W.M.
      • et al.
      DASH-Sodium Collaborative Research Group
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      • Schorr U.
      • Turan S.
      • Distler A.
      • Sharma A.M.
      Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men.
      • Sciarrone S.E.
      • Beilin L.J.
      • Rouse I.L.
      • Rogers P.B.
      A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Svetkey L.P.
      • Simons-Morton D.G.
      • Proschan M.A.
      • et al.
      Effect of the Dietary Approaches to Stop Hypertension diet and reduced sodium intake on blood pressure control.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • van Berge-Landry H.
      • James G.D.
      Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load.
      • Vollmer W.M.
      • Sacks F.M.
      • Ard J.
      • et al.
      Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      • Cappuccio F.P.
      • Markandu N.D.
      • Carney C.
      • Sagnella G.A.
      • MacGregor G.A.
      Double-blind randomised trial of modest salt restriction in older people.
      23396935803.5
       Dietary potassium intake adjustment
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • Brancati F.L.
      • Appel L.J.
      • Seidler A.J.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in African Americans on a low-potassium diet: a randomized, double-blind, placebo-controlled trial.
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • Gu D.
      • He J.
      • Wu X.
      • Duan X.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in Chinese: a randomized, placebo-controlled trial.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      • Patki P.S.
      • Singh J.
      • Gokhale S.V.
      • Bulakh P.M.
      • Shrotri D.S.
      • Patwardhan B.
      Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study.
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      • Smith S.R.
      • Klotman P.E.
      • Svetkey L.P.
      Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.
      • Whelton P.K.
      • Buring J.
      • Borhani N.O.
      • et al.
      Trials of Hypertension Prevention (TOHP) Collaborative Research Group
      The effect of potassium supplementation in persons with a high-normal blood pressure: results from phase I of the Trials of Hypertension Prevention (TOHP).
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      127527852.5
       Both salt and potassium intake adjustments
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, Phase I.
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Cook N.R.
      • Kumanyika S.K.
      • Cutler J.A.
      Effect of change in sodium excretion on change in blood pressure corrected for measurement error: the Trials of Hypertension Prevention, Phase I.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      • Nowson C.A.
      • Morgan T.O.
      • Gibbons C.
      Decreasing dietary sodium while following a self-selected potassium-rich diet reduces blood pressure.
      • Sarkkinen E.S.
      • Kastarinen M.J.
      • Niskanen T.H.
      • et al.
      Feasibility and antihypertensive effect of replacing regular salt with mineral salt-rich in magnesium and potassium in subjects with mildly elevated blood pressure.
      • Whelton P.K.
      • Kumanyika S.K.
      • Cook N.R.
      • et al.
      Trials of Hypertension Prevention Collaborative Research Group
      Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention.
      112713243012.0
      Assessed mean arterial pressure
       Dietary salt intake adjustment
      • Haythornthwaite J.A.
      • Pratley R.E.
      • Anderson D.E.
      Behavioral stress potentiates the blood pressure effects of a high sodium intake.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Dishy V.
      • Sofowora G.G.
      • Imamura H.
      • et al.
      Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.
      36407152.0
       Dietary potassium intake adjustment
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      31391761.5
       Both salt and potassium intake adjustments0NANANA
      Assessed ambulatory blood pressure
       Dietary salt intake adjustment
      • Kojuri J.
      • Rahimi R.
      Effect of “no added salt diet” on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension.
      • Schorr U.
      • Turan S.
      • Distler A.
      • Sharma A.M.
      Relationship between ambulatory and resting blood pressure responses to dietary salt restriction in normotensive men.
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      32732281.5
       Dietary potassium intake adjustment
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      290906.5
       Both salt and potassium intake adjustments0NANANA
      Assessed biomarkers, CVD and CKD progression or events, and CVD mortality
       Dietary salt intake adjustment
      Trials of Hypertension Prevention Collaborative Research Group
      Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Jula A.M.
      • Karanko H.M.
      Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild-to-moderate essential hypertension.
      • Sciarrone S.E.
      • Beilin L.J.
      • Rouse I.L.
      • Rogers P.B.
      A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Svetkey L.P.
      • Simons-Morton D.G.
      • Proschan M.A.
      • et al.
      Effect of the Dietary Approaches to Stop Hypertension diet and reduced sodium intake on blood pressure control.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • van Berge-Landry H.
      • James G.D.
      Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load.
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Dishy V.
      • Sofowora G.G.
      • Imamura H.
      • et al.
      Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.
      • Maruthur N.M.
      • Wang N.Y.
      • Appel L.J.
      Lifestyle interventions reduce coronary heart disease risk: results from the PREMIER Trial.
      • Vaidya A.
      • Bentley-Lewis R.
      • Jeunemaitre X.
      • Adler G.K.
      • Williams J.S.
      Dietary sodium alters the prevalence of electrocardiogram determined left ventricular hypertrophy in hypertension.
      18347031713.5
       Dietary potassium intake adjustment
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      532540310.0
       Both salt and potassium intake adjustments
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Chang H.Y.
      • Hu Y.W.
      • Yue C.S.
      • et al.
      Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men.
      380312486.0
      CKD = chronic kidney disease; CVD = cardiovascular disease; NA = not applicable.
      Eighteen studies involving 3470 participants receiving the intervention and 3171 controls documented the effect of changes in dietary sodium intake on laboratory parameters, markers of CVD or CKD progression, and CVD events or CVD mortality over median follow-up of 3.5 months.
      Trials of Hypertension Prevention Collaborative Research Group
      Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Jula A.M.
      • Karanko H.M.
      Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild-to-moderate essential hypertension.
      • Sciarrone S.E.
      • Beilin L.J.
      • Rouse I.L.
      • Rogers P.B.
      A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Svetkey L.P.
      • Simons-Morton D.G.
      • Proschan M.A.
      • et al.
      Effect of the Dietary Approaches to Stop Hypertension diet and reduced sodium intake on blood pressure control.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • van Berge-Landry H.
      • James G.D.
      Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load.
      • Whelton P.K.
      • Appel L.J.
      • Espeland M.A.
      • et al.
      TONE Collaborative Research Group
      Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE).
      • Burke V.
      • Beilin L.J.
      • Cutt H.E.
      • Mansour J.
      • Wilson A.
      • Mori T.A.
      Effects of a lifestyle programme on ambulatory blood pressure and drug dosage in treated hypertensive patients: a randomized controlled trial.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Dishy V.
      • Sofowora G.G.
      • Imamura H.
      • et al.
      Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses.
      • Maruthur N.M.
      • Wang N.Y.
      • Appel L.J.
      Lifestyle interventions reduce coronary heart disease risk: results from the PREMIER Trial.
      • Vaidya A.
      • Bentley-Lewis R.
      • Jeunemaitre X.
      • Adler G.K.
      • Williams J.S.
      Dietary sodium alters the prevalence of electrocardiogram determined left ventricular hypertrophy in hypertension.
      In addition, 3 studies with 803 participants receiving the intervention and 1248 controls documented the effect of changes in dietary sodium and potassium intakes on laboratory parameters, markers of CVD or CKD progression, and CVD events or CVD mortality over median follow-up of 6 months (Table 3).
      • Al-Solaiman Y.
      • Jesri A.
      • Mountford W.K.
      • Lackland D.T.
      • Zhao Y.
      • Egan B.M.
      DASH lowers blood pressure in obese hypertensives beyond potassium, magnesium and fibre.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Chang H.Y.
      • Hu Y.W.
      • Yue C.S.
      • et al.
      Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men.
      Dietary salt contributed to vascular and target organ injury as established in studies in which markers of renal injury, inflammation and oxidative stress, and vascular function measures and indices were the selected outcomes.
      • Appel L.J.
      • Espeland M.A.
      • Easter L.
      • Wilson A.C.
      • Folmar S.
      • Lacy C.R.
      Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE).
      • Del Rio A.
      • Rodriguez-Villamil J.L.
      Metabolic effects of strict salt restriction in essential hypertensive patients.
      • Dickinson K.M.
      • Keogh J.B.
      • Clifton P.M.
      Effects of a low-salt diet on flow-mediated dilatation in humans.
      • He F.J.
      • Marciniak M.
      • Visagie E.
      • et al.
      Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.
      • Slagman M.C.
      • Kwakernaak A.J.
      • Yazdani S.
      • et al.
      Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects.
      • Swift P.A.
      • Markandu N.D.
      • Sagnella G.A.
      • He F.J.
      • MacGregor G.A.
      Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.
      • Todd A.S.
      • Macginley R.J.
      • Schollum J.B.
      • et al.
      Dietary salt loading impairs arterial vascular reactivity.
      • Vaidya A.
      • Bentley-Lewis R.
      • Jeunemaitre X.
      • Adler G.K.
      • Williams J.S.
      Dietary sodium alters the prevalence of electrocardiogram determined left ventricular hypertrophy in hypertension.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Seals D.R.
      • Tanaka H.
      • Clevenger C.M.
      • et al.
      Blood pressure reductions with exercise and sodium restriction in postmenopausal women with elevated systolic pressure: role of arterial stiffness.
      The evidence from RCTs associating dietary salt or potassium intake with CVD morbidity and both CVD and all-cause mortality (Table 3 and Supplemental Table [available online at http://www.mayoclinicproceedings.org]) exhibited a direct effect of dietary salt intake on target organ damage and subsequent vascular disease events and death. On the basis of the combined evidence, we assigned level 1 to the recommendation that dietary salt intake should be limited.
      All 12 publications in which dietary potassium intake was modified reported outcome data on systolic and diastolic BP. These studies involved 752 participants receiving an intervention, 785 controls, and approximate median follow-up of 2.5 months. Three studies with 139 participants receiving an intervention, 176 controls, and approximate median follow-up of 1.5 months reported outcomes for mean arterial pressure
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      ; 2 studies with 90 participants receiving an intervention, 90 controls, and approximate median follow-up of 6.5 months reported outcomes for ambulatory BP43,48 (Table 3). Most published studies confirmed a BP-reducing effect of potassium intake by consumption of more fruits and vegetables, salt substitutes and enrichment, or supplementation, and these studies suggest that it also plays a cardioprotective role.
      • Cook N.R.
      • Obarzanek E.
      • Cutler J.A.
      • et al.
      Joint effects of sodium and potassium intake on subsequent cardiovascular disease: the Trials of Hypertension Prevention follow-up study.
      • Blumenthal J.A.
      • Babyak M.A.
      • Hinderliter A.
      • et al.
      Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Whelton P.K.
      • Buring J.
      • Borhani N.O.
      • et al.
      Trials of Hypertension Prevention (TOHP) Collaborative Research Group
      The effect of potassium supplementation in persons with a high-normal blood pressure: results from phase I of the Trials of Hypertension Prevention (TOHP).
      Hypertension Prevention Trial Research Group
      The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      • Nowson C.A.
      • Morgan T.O.
      • Gibbons C.
      Decreasing dietary sodium while following a self-selected potassium-rich diet reduces blood pressure.
      The BP-lowering benefit has been reported in normotensive
      • Brancati F.L.
      • Appel L.J.
      • Seidler A.J.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in African Americans on a low-potassium diet: a randomized, double-blind, placebo-controlled trial.
      • Braschi A.
      • Naismith D.J.
      The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers.
      • Naismith D.J.
      • Braschi A.
      The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers.
      and hypertensive
      • Cook N.R.
      • Obarzanek E.
      • Cutler J.A.
      • et al.
      Joint effects of sodium and potassium intake on subsequent cardiovascular disease: the Trials of Hypertension Prevention follow-up study.
      • Blumenthal J.A.
      • Babyak M.A.
      • Hinderliter A.
      • et al.
      Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study.
      • Akita S.
      • Sacks F.M.
      • Svetkey L.P.
      • Conlin P.R.
      • Kimura G.
      Group DA- S.T.C.R
      Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • Gu D.
      • He J.
      • Wu X.
      • Duan X.
      • Whelton P.K.
      Effect of potassium supplementation on blood pressure in Chinese: a randomized, placebo-controlled trial.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Patki P.S.
      • Singh J.
      • Gokhale S.V.
      • Bulakh P.M.
      • Shrotri D.S.
      • Patwardhan B.
      Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study.
      • Smith S.R.
      • Klotman P.E.
      • Svetkey L.P.
      Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.
      • Whelton P.K.
      • Buring J.
      • Borhani N.O.
      • et al.
      Trials of Hypertension Prevention (TOHP) Collaborative Research Group
      The effect of potassium supplementation in persons with a high-normal blood pressure: results from phase I of the Trials of Hypertension Prevention (TOHP).
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      China Salt Substitute Study Collaborative Group
      Salt substitution: a low-cost strategy for blood pressure control among rural Chinese: a randomized, controlled trial.
      • Geleijnse J.M.
      • Witteman J.C.
      • Bak A.A.
      • den Breeijen J.H.
      • Grobbee D.E.
      Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension.
      • Gilleran G.
      • O'Leary M.
      • Bartlett W.A.
      • Vinall H.
      • Jones A.F.
      • Dodson P.M.
      Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.
      • Mu J.
      • Liu Z.
      • Liu F.
      • Xu X.
      • Liang Y.
      • Zhu D.
      Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.
      individuals. One conflicting trial in prehypertensive individuals in the United Kingdom found no effect of potassium from increased fruit and vegetable consumption
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      ; however, the study had some design flaws and was seemingly underpowered. In addition, the effect of potassium supplementation and salt restriction on BP may not be additive. High potassium intake, rather, may have the greatest effect when salt intake is high because potassium supplementation did not reduce BP in hypertensive men also maintained on a low-salt diet.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      This study contrasts with another study in which participants who were advised to increase potassium intake from natural foods required fewer antihypertensive medications.
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      Five studies with 325 participants receiving an intervention, 403 controls, and approximate median follow-up of 10 months documented an effect of dietary potassium intake on laboratory parameters, markers of CVD or CKD progression, and CVD events or CVD mortality (Table 3).
      • Berry S.E.
      • Mulla U.Z.
      • Chowienczyk P.J.
      • Sanders T.A.
      Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial.
      • Grimm Jr., R.H.
      • Neaton J.D.
      • Elmer P.J.
      • et al.
      The influence of oral potassium chloride on blood pressure in hypertensive men on a low-sodium diet.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      • Siani A.
      • Strazzullo P.
      • Giacco A.
      • Pacioni D.
      • Celentano E.
      • Mancini M.
      Increasing the dietary potassium intake reduces the need for antihypertensive medication.
      • Wu G.
      • Tian H.
      • Han K.
      • Xi Y.
      • Yao Y.
      • Ma A.
      Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
      In addition to BP reduction, dietary potassium supplementation improved measures of endothelial function, vascular adherence, and cardiovascular structure and functional parameters.
      • He F.J.
      • Marciniak M.
      • Carney C.
      • et al.
      Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.
      In a large trial involving Taiwanese veterans, participants randomized to receive potassium-enriched salt lived significantly longer than their control counterparts.
      • Chang H.Y.
      • Hu Y.W.
      • Yue C.S.
      • et al.
      Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men.
      The evidence supported roles for dietary potassium intake in BP regulation and as a vascular protectant, producing a small effect on BP and a significant health benefit (level 1 recommendation).

      Discussion

      This analysis focused specifically on RCTs. The quality of the evidence of the included studies was then graded using published guidelines. Although many of these RCTs received a grade less than “A,” a sufficient number of studies were graded “A” (Supplemental Table, available online at http://www.mayoclinicproceedings.org), resulting in a level 1 recommendation for salt restriction and potassium supplementation. For some investigators, the relationship between dietary salt intake and health has been considered strong enough to make predictions regarding reduction in cardiovascular events and mortality should a population-wide reduction in dietary salt occur.
      • Coxson P.G.
      • Cook N.R.
      • Joffres M.
      • et al.
      Mortality benefits from US population-wide reduction in sodium consumption: projections from 3 modeling approaches.
      However, controversy regarding salt restriction continues. Although there now seems to be relative agreement regarding a relationship between dietary salt intake and BP, a cause-and-effect relationship between salt intake and cardiovascular event rates and mortality is more contentious. It is worth noting that a definitive preclinical study of the effect of dietary salt and potassium intakes on the life span of mammals was published more than a half century ago by Meneely and Ball.
      • Meneely G.R.
      • Ball C.O.
      Experimental epidemiology of chronic sodium chloride toxicity and the protective effect of potassium chloride.
      These investigators found that dietary salt intake in rats promoted a dose-dependent decrease in survival related to cardiovascular and renal disease. In addition, supplemental dietary potassium mitigated the effects of high salt intake.
      • Meneely G.R.
      • Ball C.O.
      Experimental epidemiology of chronic sodium chloride toxicity and the protective effect of potassium chloride.
      Studies in humans are considerably more difficult because control of potential variables is more challenging and years to decades are generally required to determine benefit, particularly in lower-risk populations. Nevertheless, the trials reviewed in this study provided high-quality evidence supporting a health benefit from restricting dietary sodium intake and increasing potassium intake.
      Most professional scientific organizations, therefore, have agreed that the US/Western-style diet contains excessive amounts of salt and that high levels of salt consumption in any population lead to higher rates of hypertension, CVD, and CVD mortality. The debate was rekindled when a high-profile prospective study reported an association between low baseline UNa excretion and higher CVD mortality.
      • Stolarz-Skrzypek K.
      • Kuznetsova T.
      • Thijs L.
      • et al.
      Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion.
      Limitations in the strength of evidence included the observational nature of the study and inherent flaws in design and methods as articulated in subsequent correspondence.
      • Bochud M.
      • Guessous I.
      • Bovet P.
      Urinary sodium excretion and cardiovascular disease mortality [letter].
      • de Abreu-Silva E.O.
      • Marcadenti A.
      Urinary sodium excretion and cardiovascular disease mortality [letter].
      • Labarthe D.R.
      • Briss P.A.
      Urinary sodium excretion and cardiovascular disease mortality [letter].
      One issue of particular concern was the undercollection of 24-hour urine samples in individuals in the lowest tertile of UNa excretion, as indicated by lower creatinine excretion, potassium levels, and 24-hour urine volume.
      • He F.J.
      • Appel L.J.
      • Cappuccio F.P.
      • de Wardener H.E.
      • MacGregor G.A.
      Does reducing salt intake increase cardiovascular mortality?.
      The conclusion of the present study also differs from that of a recent meta-analysis that evaluated whether BP reduction was an explanatory factor in any effect of dietary salt interventions on mortality and CVD outcomes identified.
      • Taylor R.S.
      • Ashton K.E.
      • Moxham T.
      • Hooper L.
      • Ebrahim S.
      Reduced dietary salt for the prevention of cardiovascular disease.
      In that report, the criteria for inclusion included (1) randomization with follow-up of at least 6 months, (2) an intervention that reduced dietary salt intake (restricted salt dietary intervention or advice to reduce salt intake), (3) adults, and (4) mortality or cardiovascular morbidity data available.
      • Taylor R.S.
      • Ashton K.E.
      • Moxham T.
      • Hooper L.
      • Ebrahim S.
      Reduced dietary salt for the prevention of cardiovascular disease.
      Of 7 trials identified, the authors concluded that the combined experimental evidence was insufficient to determine the health effect of reducing salt intake.
      • Taylor R.S.
      • Ashton K.E.
      • Moxham T.
      • Hooper L.
      • Ebrahim S.
      Reduced dietary salt for the prevention of cardiovascular disease.
      A weakness of that meta-analysis was the inclusion of a trial on heart failure in which sick participants were receiving intensive drug regimens. Participants in that trial were treated with furosemide (250-500 mg twice daily) as well as spironolactone, angiotensin-converting enzyme inhibitors, β-blockers, and digitalis. In this heavily medicated population, a reduction in dietary salt intake was associated with an increase in mortality.
      • Paterna S.
      • Gaspare P.
      • Fasullo S.
      • Sarullo F.M.
      • Di Pasquale P.
      Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?.
      Although the validity of that particular study was not doubted, it was not included in the present analysis because of the severity of illness of the population in the study.
      In an observational analysis of ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease), O'Donnell et al
      • O'Donnell M.J.
      • Yusuf S.
      • Mente A.
      • et al.
      Urinary sodium and potassium excretion and risk of cardiovascular events.
      noted a J-shaped relationship between UNa excretion and risk of a composite outcome of CVD events and mortality. The J-shape is a result of a contradictory inverse relationship in 12% of participants with an estimated UNa excretion of less than 3000 mg/d. ONTARGET and TRANSCEND consisted of participants older than 55 years with a high risk of stroke and CVD during follow-up.
      • O'Donnell M.J.
      • Yusuf S.
      • Mente A.
      • et al.
      Urinary sodium and potassium excretion and risk of cardiovascular events.
      At baseline, 70% had hypertension, almost 40% had diabetes, almost half had a history of myocardial infarction, and more than 1 in 5 had a history of stroke.
      • O'Donnell M.J.
      • Yusuf S.
      • Mente A.
      • et al.
      Urinary sodium and potassium excretion and risk of cardiovascular events.
      The potential for an error in the assessment of salt intake is likely because a single morning spot urine collection was used to determine the 24-hour UNa excretion estimate. Values obtained from spot urine specimens are not a suitable alternative for 24-hour collections, especially in sick patients, such as those included in the study. Medications such as diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers can greatly affect sodium levels in spot urine collections, and the use of these drugs is more likely in those at greatest risk for CVD and is, thus, subsequently linked to a greater potential for measurement error. Another study in patients with type 2 diabetes mellitus found that lower 24-hour UNa excretion was associated with increased all-cause and cardiovascular mortality.
      • Ekinci E.I.
      • Clarke S.
      • Thomas M.C.
      • et al.
      Dietary salt intake and mortality in patients with type 2 diabetes.
      At baseline, participants with the lowest tertile of salt intake in that study were significantly older, had a longer disease duration, and had a reduced estimated glomerular filtration rate compared with the intermediate and highest salt intake tertiles.
      • Ekinci E.I.
      • Clarke S.
      • Thomas M.C.
      • et al.
      Dietary salt intake and mortality in patients with type 2 diabetes.
      In addition, the methods used to ensure adequacy of urine sample collections were not detailed. Paradoxical findings, such as those described by O'Donnell et al
      • O'Donnell M.J.
      • Yusuf S.
      • Mente A.
      • et al.
      Urinary sodium and potassium excretion and risk of cardiovascular events.
      and Ekinci et al,
      • Ekinci E.I.
      • Clarke S.
      • Thomas M.C.
      • et al.
      Dietary salt intake and mortality in patients with type 2 diabetes.
      can result when illness is the cause rather than the consequence of the level of salt intake. Sick individuals have a higher risk of disease progression and associated outcomes, and, as one becomes more ill, caloric intake along with salt intake can decrease dramatically. Although severe restrictions in dietary sodium intake might contribute to adverse outcomes in patients with multiple comorbidities, this classic framework, as noted by Whelton et al,
      • Whelton P.K.
      • Appel L.J.
      • Sacco R.L.
      • et al.
      Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations.
      is potentially one of reverse causality.
      Protocol-based investigations of dietary salt or potassium relationships in studies such as the INTERSALT (International Study of Salt and Blood Pressure), the Trials of Hypertension Prevention phases I and II, the Trial of Nonpharmacologic Interventions in the Elderly, and the DASH-Sodium trial all measured 24-hour urinary estimation of electrolytes. In contrast, some of the newer publications used data previously collected in studies that had a different purpose. Although the availability of and access to observational data sets are more convenient and less expensive, one must take caution with interpretation of results as they are not specifically designed to explore the dietary salt risk or dietary potassium benefit regarding CVD prevention. Therefore, only meticulous protocol-based studies of sufficient quality should guide stakeholders' decisions in contributing to public policy.

      Implications for Clinicians and the General Public

      In the United States, current recommendations and guidelines
      • Appel L.J.
      • Frohlich E.D.
      • Hall J.E.
      • et al.
      The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association.
      emphasize a reduction in dietary salt intake and a simultaneous increase in dietary potassium consumption. The Institute of Medicine, the American Heart Association, and the US Department of Health and Human Services/US Department of Agriculture recommend limiting salt intake. For potassium, the data suggest that supplementation is best achieved through alterations in the diet. The analyses provided in the present study support the application of these recommendations to the population as a whole, with some caveats. The first potential limitation is that the clinician should be aware that patients with severe heart failure requiring high-dose diuretic and medication therapy will not benefit from salt restriction.
      • Paterna S.
      • Gaspare P.
      • Fasullo S.
      • Sarullo F.M.
      • Di Pasquale P.
      Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?.
      The unusual patients with salt-wasting tubulopathies should not undergo salt restriction without close supervision. Patients with advanced CKD may be at risk for hyperkalemia should the daily intake of potassium increase to 4700 mg. Additional potentially vulnerable populations that require individualized dietary recommendations might include patients with multiple comorbid conditions. Another limitation is that the evidence base is insufficient to provide a definitive lower limit for dietary salt intake and upper limit for potassium intake. It seems unlikely that additional RCTs to guide population-based therapy will follow because trials that examine clinical end points such as mortality are expensive, requiring large numbers of participants and taking years to achieve an adequate number of study outcomes. Therefore, it seems prudent to recommend more stringent reductions, particularly in higher-risk, potentially salt-sensitive individuals, such as black patients, individuals older than 51 years, and patients who have hypertension or prehypertension, before the onset of severe end-organ damage. Finally, unless there is a contraindication in selected patients or conflicting clinical data begin to emerge, the evidence in preclinical studies of the detrimental effect of dietary salt on the vasculature independent of BP suggests that a practical choice for clinicians may be to encourage all patients to adhere to these guidelines to promote health.

      Supplemental Online Material

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